Memory B cells that differentiate into antigen presenting and antibody-producing cells are important for long-term immunity to natural antigens and vaccines and may play a key role mediating the clinical manifestations of autoimmune diseases. Memory B cells themselves, however, are typically rare and hence poorly understood. Using mouse systems developed in our laboratory that overcome significant barriers to the study of B cell memory, we compared gene expression between memory B cells and their naive precursors using Affymetrix microarrays and have confirmed the differential expression of several conceptually important families at the mRNA and protein level. Based on known functions of these genes in other cell types, we have developed hypotheses about how their functions determine properties of memory B cells. Here, we propose to test the hypotheses that: 1) leukemia inhibitory factor signaling regulates memory B cell self-renewal and differentiation and 2) the B7 family member PD-L2 on memory B cell plays a central role modulating the secondary response to antigenic stimulation. In the long-term, a better understanding of the events required for memory B cell self-renewal, differentiation and activation will lead to improved vaccination strategies. My immediate career goal, is to acquire the training and develop the systems required to address these hypotheses of B cell memory as an Assistant Professor of Dermatology at Yale. This proposed 5-year mentored program will provide the basis for many long-term projects and collaborations and will foster my development into an independent investigator. RELEVANCE: The ability to develop "immunological memory" to infectious diseases is critical for health and survival. These proposed studies will help elucidate how "memory" functions in order to better understand natural immunity and improve vaccine design.